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Thứ Hai, 18 tháng 4, 2016

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Imatinib

Imatinib
Imatinib2DACS.svg
Ball-and-stick model of the imatinib molecule
Systematic (IUPAC) name
4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide
Clinical data
Trade namesGleevec, Glivec
AHFS/Drugs.commonograph
MedlinePlusa606018
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    administration
    Oral
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability98%
    Protein binding95%
    MetabolismHepatic (mainly CYP3A4-mediated)
    Biological half-life18 h (imatinib)
    40 h (active metabolite)
    ExcretionFecal (68%) and renal (13%)
    Identifiers
    CAS Number152459-95-5 Yes
    220127-57-1 (mesilate)
    ATC codeL01XE01 (WHO)
    PubChemCID 5291
    IUPHAR/BPS5687
    DrugBankDB00619 Yes
    ChemSpider5101 Yes
    UNIIBKJ8M8G5HI Yes
    KEGGD08066 Yes
    ChEBICHEBI:45783 Yes
    ChEMBLCHEMBL941 Yes
    Chemical data
    FormulaC29H31N7O
    Molar mass493.603 g/mol
    589.7 g/mol (mesilate)
      (verify)
    Imatinib (INN), marketed by Novartis asGleevec (Canada, South Africa and the USA) or Glivec (Australia, Europe and Latin America), investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+chronic myelogenous leukemia(CML).[1]
    In order to survive, cells need signaling through proteins (signal cascade) to keep them alive. Some of the proteins in this cascade use a phosphate group as an "on" switch. This phosphate group isadded by a tyrosine kinase enzyme. In healthy cells, these tyrosine kinase enzymes are turned on and off as needed. In Ph-positive CML cells, one tyrosine kinase enzyme, BCR-Abl, is stuck on the "on" position, and keeps adding phosphate groups. Imatinib blocks this BCR-Abl enzyme, and stops it from adding phosphate groups. As a result, these cells stop growing, and even die by a process of cell death (apoptosis).[2] Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug's action.[3] In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.[4]
    Due in large part to the development of Gleevec and related drugs having a similar mechanism of action, the five year survival rate for people with chronic myeloid leukemia nearly doubled from 31% in 1993 (before Gleevec's 2001 FDA approval) to 59% for those diagnosed between 2003 and 2009.[5] Compared to older drugs imatinib has a relatively benign side effect profile, allowing many patients to live a normal lifestyle.[6] Median survival for imatinib-treated people withgastrointestinal stromal tumors (GIST) is nearly 5 years compared to 9 to 20 months in the pre-imatinib-era.[7]
    Physicians have written that the cost of imatinib, averaging $120,000 a year in 2016, is excessive. In the USA, the patent protecting the active principle expired on 4 January 2015 while the patent protecting the beta crystal form of the active principal ingredient will expire on 23 May 2019. In India, the patent was rejected, in an Indian Supreme Court decision in 2013.[8]
    It is on the World Health Organization's List of Essential Medicines, a list of the medications needed to cover the majority of health care needs in a health system.[9] The developers of imatinib were awarded the Lasker Award in 2009 and the Japan Prize in 2012.[10][11] Gleevec is the beta crystalline form of imatinib mesilate, the mesylate salt of imatinib.

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